• •

  Neuromodulators are endogenous or exogenous molecules that act modulating the synthesis and/or release of one or more neurotransmitters, the activity of ion channels and neural potentials, and the activation or blockade of presynaptic and postsynaptic receptors in the CNS or PNS.

• •

  We recommend adopting the term “neuromodulators” proposed by the Rome Foundation for describing the medications that act on the gut-brain axis.

Motor, sensory, and gastrointestinal (GI) secretory activity is connected to and regulated by cortical brain activity through a system of afferent and efferent neuronal pathways called the gut-brain axis (GBA). This axis consists of a complex bidirectional network, formed by reflex loops that control the homeostasis of GI function, and is impacted by the enteric microbiota/microbiome.6,7 The GBA is divided into a brain connectome that includes the CNS, with different involuntary interconnected areas involved in different mental processes, such as discrimination and localization (primary sensorimotor cortex), processing of emotions (brain stem), behavior (medial thalamus, cingulate cortex, and insula regions), the blood-brain barrier, afferent and efferent branches, the spinal dorsal horn, the autonomous nervous system (ANS), the enteric nervous system (ENS), and a gut connectome made up of the microbiota, microbiome, epithelial barrier, neuroreceptors, inflammatory cells, and immune mediators.6,7 Dysfunction in one or several of those mechanisms can result in motor, secretory, autonomic tone, hypothalamic-pituitary-adrenal axis, and central and peripheral sensory alterations that clinically translate into one or more DGBI, which can affect one or more segments of the GI tract.1,8,9 Among the multiple pathophysiologic mechanisms of the DGBI, the most common are alterations in the central processing of stimuli arising from the target organ, neuroimmune dysfunction, and visceral hypersensitivity, and even though there are drugs directed at other mechanisms, such as dysmotility or altered intestinal secretion, treatment is based on neuromodulators.1,8,10 Neuromodulators are considered to be any endogenous or exogenous molecule, that without being accumulated and released by nerve endings, acts presynaptically, modulating the synthesis and/or release of one or more neurotransmitters, and secondarily regulates ion channel activity and membrane potentials in neural cells through the activation or blockade of different presynaptic and postsynaptic receptors in the CNS or PNS. Some exogenous devices with similar properties can also be classified as neuromodulators.8,11,12 Due to the heterogeneity of pharmacologic groups considered neuromodulators and to the fact that they are a fundamental part of treatment of DGBI, the Rome Foundation has proposed re-labeling and redefining the terminology of medications acting within that system, coining the name neuromodulators, instead of referring to them as antidepressants, antipsychotics, anticonvulsants, or neurolytic agents, given that the doses prescribed for inducing neuromodulation are different from their other indications.13 There is a marked heterogeneity regarding the knowledge, attitude, and level of practice among primary care physicians and some gastroenterologists, as was recently described at a university hospital in Korea, where less than 30% of physicians prescribed neuromodulators due to little familiarity with the pharmacologic group.14

• •

  Neuromodulation is the physiologic process by which a stimulus regulates the neuronal population, activity, and functions through the action of one or more neurotransmitters that can activate or block receptors, to induce a modulating effect.

• •

  Neuromodulators have the capacity to modulate pain perception and induce neuroplasticity due to the effect on one or more neurotransmitters and postsynaptic receptors at the central or peripheral level.

Neuromodulators affect ascending neural transmission (they interfere with the brain circuits related to pain, emotional and cognitive, and interfere with the transmission of pain in the spinal dorsal horn), as well as descending neural transmission (control of projections arising from diverse brain structures, mediated by serotonergic, noradrenergic, and opioidergic receptors). At the synaptic level, they induce a rapid increase in the action of one or more monoamines, according to each subgroup, causing their accumulation in the synaptic space. A second mechanism is delayed downregulation or desensitization of the postsynaptic receptors of the respective receptor. Neuromodulators have been described to induce neuroplasticity that involves anti-neurodegenerative properties, particularly in syndromes associated with chronic pain. One of the mechanisms appears to be cortical neuron loss and neurogenesis induction, through an increase in brain-derived neurotropic factor (BDNF) levels, given that over time, chronic pain, depression, anxiety, and other forms of emotional stress lead to loss of cortical neuron density, a process that neuromodulators can reverse.1,8,15

The mechanism of action in the GI tract varies, according to each neuromodulator subgroup, and can include partial or total stimulation and/or inhibition of one or more presynaptic and postsynaptic serotonergic, muscarinic, cholinergic, or noradrenergic transporters or receptors, with therapeutic effects (increase or decrease in motility and gastrointestinal tone, gastric accommodation, antinociceptive effect), as well as adverse effects (somnolence, dry mouth, constipation, diarrhea, urinary retention, weight gain) that vary, depending on the stimulated or inhibited receptor.1

• •

  Therapeutic (and adverse) effects of neuromodulators depend on their agonism or antagonism on one or more receptors, which can induce an increase or decrease in the reuptake of different neurotransmitters.

Pharmacodynamics refers to the mechanisms and effects of medications on biologic functions in the organism, i.e., what they do in the body and how they do it. In order to have an effect, neuromodulators have to reach the target cells and bind to one or more receptors that are specialized proteins located inside the cell or on its membrane. After binding to a signaling molecule, called a “ligand”, they can alter its form or activity, according to the effect the ligand has on the receptor, and there are two large pharmacologic categories: agonists and antagonists.16

Agonist. Any substance that mimics the action of the signaling ligand by binding to a receptor and activating it.

Antagonist. Any substance that binds to a receptor without activating it, impeding its activation by other signals, i.e., decreasing the capacity of the receptor to be activated by another agonist, or blocking it. Receptor antagonists can be classified into reversible and irreversible. Reversible antagonists are easily separated from their receptor; irreversible antagonists form a stable, permanent, or almost permanent, bond with their receptor.

Reuptake. This process consists of the reabsorption of neurotransmitters or other substances, after been released in the synapse. Reuptake is a form of neurotransmitter inactivation, which is crucial for the termination of synaptic signaling and for regulating the concentration of neurotransmitters available in the synaptic space, which in turn, has direct implications on modulating both central and peripheral nervous system function. In the CNS, reuptake processes are especially relevant for neurotransmitters, such as serotonin, noradrenaline, and dopamine.

• •

  Neuromodulators are classified according to their chemical structure, pharmacologic group, and site of action (central or peripheral).

• •

  Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), azapirones, atypical antipsychotics, and anticonvulsants are central neuromodulators. Delta-ligands are peripheral neuromodulators.

• •

  The concept of the neuromodulator and its indication should be explained to the patient, avoiding the use of terms, such as antidepressant, anxiolytic, antipsychotic, and neurolytic, to prevent confusion with other indications for the same drug.

Neuromodulators are classified according to their chemical structure, pharmacologic group, and site of action (central or peripheral) (Table 1).2,11,17 Due to the heterogeneity of groups considered neuromodulators, most of those drugs have more than one therapeutic indication, and include treatment of psychiatric disorders, such as depression, anxiety, obsessive-compulsive disorder (OCD), schizophrenia, neuropathy, and convulsive crises, among others. Therefore, the physician must take the time to explain to the patient, not only the pathophysiologic mechanisms behind pain, but also the neuromodulation mechanisms of each of those pharmacologic groups and their desired clinical effect, specifying the fact that the primary indication for their use in gastroenterology is to modulate pain perception, in an effort to avoid confusion and stigma on the part of patients.8,18

• •

  The antinociceptive effect of each group of neuromodulators may differ, depending on the activation or inhibition of different receptors and neurotransmitters. Some can have an effect on gastrointestinal motility.

In general, neuromodulators modify the synaptic action of one or more of the three main monoamines: dopamine, serotonin, and noradrenaline (Table 1). The mechanism of action of each group of neuromodulators may vary due to their pharmacologic structure. Each subgroup can partially or totally stimulate and/or inhibit one or more presynaptic and postsynaptic serotonergic (5-HT), histaminergic, muscarinic, or noradrenergic receptors, with pharmacologic effects on motility, secretion, and visceral analgesia. In many cases, the adverse effects on GI motility and secretion may help control secondary symptoms such as constipation, diarrhea, or weight loss.2,11

Tricyclic antidepressants (TCAs). They induce antagonism and inhibition of multiple presynaptic (α2) and postsynaptic (5-HT2, 5-HT3, H1, muscarinic-1, α1) receptors, which translates into a decrease in GI motility (cholinergic, noradrenergic effect) and a central antinociceptive effect. Imipramine, amitriptyline, nortriptyline, desipramine, doxepin, and trimipramine belong to this group.11

Selective serotonin reuptake inhibitors (SSRIs): They selectively block the presynaptic 5-HT transporter, resulting in an increase in GI motility with no significant effect on sensitivity (they have little analgesic effect). The SSRIs are citalopram, escitalopram, sertraline, fluoxetine, fluvoxamine, and paroxetine.19 Some, such as fluoxetine (5-HT2C antagonism) or paroxetine (anticholinergic effect), possess a second mechanism of action.2

Serotonin and norepinephrine reuptake inhibitors (SNRIs). They block the presynaptic 5-HT and presynaptic noradrenaline transporters. Venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran belong to this group. Venlafaxine induces 5-HT blockade at low doses and noradrenergic reuptake inhibition at high doses (>225 mg) and duloxetine has the same affinity for the 5-HT and noradrenergic transporters, whereas milnacipran has a greater noradrenaline reuptake inhibitory effect. The antinociceptive effects of the SNRIs appear to be superior to those of the SSRIs.2,20

Tetracyclic agents. They increase noradrenergic activity, with a specific increase in serotonergic activity through the presynaptic neuronal antagonism of the noradrenaline and 5HT auto and heteroreceptors. The antidepressant effects are a result of 5-HT2A and 5-HT2C antagonism, whereas the GI effects are a result of 5-HT3 antagonism. Mirtazapine, mianserin, amoxapine, and trazodone belong to this group.2 At low doses, mirtazapine exhibits H1 antagonism, which can cause sedation, whereas 5-HT2C antagonism stimulates appetite and weight gain.21

Azapirones. They are partial presynaptic and postsynaptic 5HT1 receptor agonists and have a certain affinity for the 5HT2 receptor, as well as a moderate affinity for the dopamine D2 receptors.22 They are considered non-benzodiazepine anxiolytics. Buspirone and tandospirone belong to this group and have a similar mechanism of action.2

Atypical antipsychotics. They are a heterogeneous medication class, also known as second-generation antipsychotics. Sulpiride, amisulpride, levosulpiride, quetiapine, olanzapine, risperidone, aripiprazole, brexpiprazole, and clozapine belong to this group. Their mechanism of action is through dopamine D2 receptor antagonism, as well as partial D2 agonism (sulpiride, amisulpride, levosulpiride), partial 5-HT1A agonism (quetiapine), and 5-HT2A antagonism (olanzapine, quetiapine).2 All of these additional mechanisms of action reduce the risk of adverse effects, particularly extrapyramidal ones. Some first-generation antipsychotics, also called neuroleptics, such as chlorpromazine or trifluoperazine, have been utilized for the treatment of nausea but they tend to be more frequently associated with extrapyramidal side effects.23

Anticonvulsants. They are a heterogenous group divided into 8 drug subgroups, according to their mechanism of action. Some have more than one mechanism, such as the repeatedly-activated sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine), gamma-aminobutyric acid (GABA) analogues and potentiators (phenobarbital, benzodiazepines, baclofen), glutamate modulators (topiramate, lamotrigine, felbamate), T calcium channel blockers (ethosuximide, valproic acid), N and L-type calcium channel blockers (lamotrigine, topiramate, zonisamide, valproic acid), H-current modulators (gabapentin, lamotrigine), carbonic anhydrase inhibitors (topiramate, zonisamide), and specific binding site blockers (gabapentin, levetiracetam).8,24

Delta-ligands or α2-delta ligands. Delta-ligands block the α2-delta subunit of the presynaptic voltage-dependent calcium channels in the medullary dorsal horn, and so they are considered peripheral neuromodulators. They have no effect on GI motility. Pregabalin and gabapentin belong to this group. As previously stated, gabapentin is also an H-current modulator, and therefore, is classified as an anticonvulsant, and may have a partial central neuromodulating effect.25,26

• •

  TCAs (imipramine, amitriptyline, nortriptyline, desipramine, doxepin, trimipramine) have a visceral analgesic effect and decrease GI motility and secretion. Their main indication is for pain as the predominant symptom or diarrhea-associated DGBI.

TCAs have several mechanisms of action: they possess antagonism and inhibition of multiple presynaptic (α2) and postsynaptic (5-HT2, 5-HT3, H1, muscarinic-1, α1) receptors that result in a decrease in GI motility (cholinergic, noradrenergic, serotonergic effect) and a central antinociceptive effect.22 Their analgesic properties are due to a combination of 5-HT and noradrenaline reuptake inhibition properties. Because of their dual action, TCAs theoretically have a more potent analgesic effect, compared with other neuromodulators, such as SSRIs.27 In addition, they act as muscarinic-1 receptor antagonists, associating them with slow orocecal transit (amitriptyline, imipramine, desipramine).2,28

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  SSRIs (citalopram, escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine) increase GI motility but have no effect on visceral sensitivity/analgesia. They are useful for treating anxiety, phobias, and DGBI-associated obsessive-compulsive disorder (OCD).

The mechanism of action SSRIs have in common is through selective blockade of the presynaptic 5-HT transporter, resulting in increased GI motility but with no significant effect on sensitivity.19 Acute serotonin transporter inhibition in humans increases colonic phasic contractility and the frequency of high-amplitude propagated contractions, also increasing colonic compliance and suppressing the colonic tonic response to foods, whereby SSRIs increase gastric and intestinal propulsive motility.29 They may be used for reducing the anxiety or hypervigilance associated with different DGBI.

• •

  SNRIs (duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran) inhibit gastro-colonic tone to a lesser degree than TCAs and have a visceral analgesic effect. They are useful for disorders with a predominance of pain, including associated conditions (fibromyalgia, headache) or when TCAs are not tolerated.

SNRIs act as 5-HT3 receptor antagonists, delaying gastric emptying and decreasing colonic transit time.2 Their safety profile is more favorable than that of the TCAs, so they are an alternative for treatment of disorders associated with chronic pain, when TCAs are not tolerated. The antinociceptive effects of SNRIs appear to be superior to those of SSRIs.30

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  Tetracyclic agents (mirtazapine, mianserin, amoxapine, trazodone) have a relaxing effect on the gastric fundus, and their potential use is in disorders associated with satiety, nausea, and weight loss.

The GI effects of the tetracyclic agents are due to their specific mode of action on noradrenergic and serotonergic receptors, particularly, increased noradrenergic activity and 5-HT1 and 5-HT3 antagonism, which can explain their effects on reducing nausea, pain, and diarrhea. However, because histamine plays an important role in satiety and appetite regulation, its inhibition is associated with weight gain. There is evidence on their inhibition of gastric and colonic tone, but more studies are needed to evaluate their effect on GI motility.31

• •

  Azapirones (buspirone, tandospirone) increase esophageal contractility and have a predominant effect on gastric accommodation, with less evidence of an antinociceptive effect. Their potential use is in early satiety, postprandial fullness, nausea, and associated anxiety.

Azapirones are nonselective postsynaptic 5-HT1A receptor agonists, presynaptic D2, D3, and D4 receptor antagonists, and partial α1-adrenergic agonists. They have effects on gastric accommodation and relaxation, no effects on esophageal or colonic motility, and there is less evidence of an antinociceptive effect. Studies on dyspepsia have shown their usefulness for improving symptoms in patients with early satiety, postprandial fullness, and nausea. Because they are non-benzodiazepine anxiolytics, they are useful when there is associated anxiety.32,33

• •

  Atypical antipsychotics (sulpiride, levosulpiride, olanzapine, quetiapine, aripiprazole, brexpiprazole, risperidone, clozapine, flupentixol) and some typical antipsychotics (chlorpromazine, trifluoperazine) have different therapeutic and adverse effects according to subtype, and their main use in DGBI is control of nausea and vomiting. Levosulpiride improves gastric relaxation and has a mixed prokinetic and anxiolytic effect.

There is no evidence on the effect of atypical antipsychotics on GI motility in healthy subjects. Nevertheless, due to their dopamine and serotonergic antagonist effect, and in some cases their muscarinic effect, they have been used to treat nausea and vomiting associated with different conditions.23 Sulpiride and levosulpiride are occasionally used to treat functional dyspepsia (FD) and gastroparesis (GP) because of their effects on gastric emptying.34,35 There is evidence of improvement in nausea and vomiting with olanzapine in different disorders, including postoperative states and after the administration of chemotherapy.36

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  There is limited evidence on the effects of anticonvulsants (carbamazepine, oxcarbazepine, baclofen, lamotrigine, valproic acid, topiramate) on GI sensitivity and motility. Topiramate is useful for preventing different forms of headache and cyclic vomiting syndrome.

Anticonvulsants have a potential analgesic effect but evidence on their effectiveness in acute and chronic pain is limited,37 and there is insufficient evidence on their effects on GI motility. Topiramate has been used as a prophylactic agent in different forms of headache, and more recently, in cyclic vomiting.38,39 Gabapentin is a dual-action drug, given that it is considered an anticonvulsant that blocks a specific binding site, but its main mechanism of action is as a peripheral neurolytic agent. Its principal role is pain control in neuropathy, albeit little is known about its central antinociceptive effect.37

• •

  Delta-ligands (pregabalin, gabapentin) are useful in DGBI-related neuropathic pain and associated diseases, such as fibromyalgia.

Pregabalin and gabapentin have a similar mechanism of action, acting by binding to calcium channels and modulating the flow of calcium, in addition to influencing GABAergic receptor-associated neurotransmission. Pregabalin has an analgesic and anxiolytic effect, and gabapentin has an analgesic, anxiolytic, as well as an anticonvulsant effect.40 The effect of delta-ligands on GI sensitivity and motility has yet to be elucidated, but due to their known mechanism of action at the level of the CNS, they appear to have an effect on neuromodulation.25

• •

  Some neuromodulators may be useful for controlling psychiatric comorbidities in DGBI, including anxiety, hypervigilance, OCD, and depression, among others.

In addition to their antinociceptive effect, neuromodulators may be used in DGBI to treat associated comorbidities, including extragastrointestinal manifestations, such as fibromyalgia, migraine, and interstitial cystitis, or in patients with psychiatric comorbidities. These drugs may reduce anxiety, hypervigilance, selective attention, and catastrophizing associated with GI symptoms and are indicated for the treatment of other conditions, such as OCD and depression. They can also reverse cortical neuron loss and induce neurogenesis, because over time, chronic pain, depression, anxiety, and other forms of emotional distress are conducive to cortical neuron density loss. As previously stated, central neuromodulators can reverse that process by increasing BDNF levels, leading to an increase in neurogenesis.11,12

Table 2 shows the recommended doses of each of the different types of neuromodulators utilized in DGBI.

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  Neuromodulators may be considered in combination with speech therapy and diaphragmatic breathing for the treatment of gastric belching (GB) and supragastric belching (SGB) associated with GERD (baclofen) and psychiatric comorbidity associated with DGBI (mirtazapine and buspirone).

The treatment of disorders associated with gastric belching (GB), as well as supragastric belching (SGB), is based on their association with other disorders (GERD, dyspepsia) or the pathophysiologic mechanism involved (learned behavior, psychologic factors, or transitory lower esophageal sphincter [LES] relaxation), or both. In SGB, the clinician should explain the pathophysiologic mechanisms leading to belching, in order to establish an understanding and create awareness of the maneuvers of the passage of air into the esophagus (psychoeducation), diaphragmatic breathing exercises, cognitive therapies, and speech therapies. In the majority of cases, those measures are sufficient for the control or symptom improvement of SGB.167–170 The usefulness of neuromodulators has not been shown in isolated GB or SGB, even though central neuromodulators could be useful when the conditions are associated with psychiatric disorders, such as anxiety or OCD linked to symptom onset or persistence, or even to anxiety related to associated bloating. Baclofen may be useful when SGB is associated with GERD due to its inhibitory effect on transitory LES relaxations.167,171,172 In GB associated with PDS-FD, the use of gastric fundus relaxants, such as mirtazapine or buspirone, might be useful.32

• •

  Neuromodulators may be considered in combination with behavioral therapy focusing on diaphragmatic breathing for patients with rumination (TCAs), rumination associated with GERD (baclofen), or psychiatric comorbidities (SSRIs).

Rumination is a disorder characterized by recurrent effortless regurgitation of recently ingested food, that is subsequently re-chewed and re-swallowed, not preceded by retching, and subsides when the regurgitated material becomes acidic.140,173 The mechanism of onset is a sudden increase in intragastric pressure that triggers LES relaxation, which induces retrograde movement of the gastric contents into the esophagus.174 A primary maintenance pathway and several potential secondary pathophysiologic mechanisms have been described, and they may include premonitory urge, learned associations, response to specific stimuli, or an additional condition, such as SGB (supragastric rumination) or GERD (secondary rumination).175 Treatment of rumination is based on behavioral therapy that focuses on diaphragmatic breathing, because using the diaphragm to breathe during the postprandial period competes with the desire to regurgitate. The therapy can be combined with electromyography-controlled biofeedback, in order to decrease intercostal and anterior abdominal activity.173,176 Only one study has evaluated the usefulness of TCAs in rumination. Forty-four patients with rumination, according to Rome IV, received a TCA plus instructions and support for carrying out diaphragmatic breathing, and were followed for 3 months. After a mean follow-up period of 8.8 months, 90.9% of patients reported symptom improvement and 45% of them reported more than 80% improvement. In addition, weight was stabilized in 80.6% of the patients. Because previously published response rates with diaphragmatic breathing alone are high, the net effect of adding a neuromodulator to the behavioral therapy is not known.177 With the exception of that single study, current evidence does not support the effectiveness of neuromodulators for reducing rumination episodes, and therefore, they are not recommended as monotherapy. Some guidelines suggest their use only for treating psychiatric comorbidities, following the indications for the associated DGBI.175

Fig. 2 summarizes the principal neuromodulators recommended for managing gastroduodenal DGBI.

Figure 2.

Gastroduodenal disorders.

ꝉ: EPS/PDS overlap or weight loss ¶: Adjuvant symptomatic therapy, ⱡ: Associated with PDS, †: Associated with GERD.

Classification and therapeutic approaches for functional gastroduodenal disorders, including treatment lines based on efficacy and the adjunctive role in therapy.

(0.41MB).

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  Neuromodulators may be considered in patients who do not respond adequately to conservative treatments for managing functional anorectal pain.

According to the Rome IV criteria, the painful anorectal syndromes include levator ani syndrome (LAS), nonspecific functional anorectal pain (FARP), and proctalgia fugax. LAS and nonspecific FARP are characterized by the presence of chronic or recurrent rectal pain or sensation of discomfort that lasts at least 30 minutes, with no evidence of a structural or systemic explanation for the symptoms, and is distinguished by the presence (LAS) or absence (nonspecific FARP) of pain upon palpating the levator ani muscle.200 Proctalgia fugax is characterized by acute recurrent anorectal pain, in the absence of organic pelvic or proctologic disease. It is separate from bowel movements and lasts fewer than 30 minutes, with complete remission between episodes. Neuromodulators may be considered a therapeutic option for the management of functional anorectal disorders, in patients who do not adequately respond to conservative treatments, such as pelvic floor physical therapy or stress management. Neuromodulators, such as TCAs or SSRIs, as well as gabapentin, may be used due to their analgesic properties and may be combined with muscle relaxants, such as cyclobenzaprine. No RCTs have been conducted that confirm the efficacy of medical therapies in that particular group of patients, and their side effects could limit their usefulness. However, different groups of experts (e.g., C. Knowles at Cleveland Clinic London) use low doses of clomipramine in patients with coexisting anxiety disorders.201

Fig. 3 summarizes the main neuromodulators recommended for managing intestinal and anorectal DGBI.

Figure 3.

Intestinal and anorectal disorders.

Classification and treatment strategies for functional intestinal and anorectal disorders, organized in treatment lines based on clinical efficacy and therapeutic use.

(0.35MB).

• •

  We recommend teaching communication skills, such as active listening and emotion validation, to guarantee comprehensive and empathetic care, improving patient satisfaction, perception of physician approachability, and treatment adherence.

  Table 3.

  Communication strategy.

  Recommended (what to do)

  Not recommended (what not to do)

  • Recognize symptoms and their severity • Understand the patient and the effect symptoms have on him/her • Show the patient that you believe he/she has symptoms. They are real and physically experienced • Be honest when a patient has unusual or inconsistent symptoms • Think of ways to empower the patient • Explain the connections between physical and psychologic stress with clear and positive language • Negotiate an explanation that takes culture into account • Normalize: all symptoms are biopsychosocial

  • Tell the patient that there is nothing bad • Tell the patient that the symptoms are normal • Repeatedly calm the patient (unending cycle) • Tell the patient there is nothing that can help him/her • Give normal test results and calm the patient, thinking this will help him/her • Suggest to the patient that the “real” cause of symptoms is psychologic • Offer simplified and dichotomous explanations that are purely psychologic or somatic
• •

  We recommend establishing two-way communication between physicians and patients, to improve understanding and involve the patients in their own treatment and adherence. We recommend explaining the pathophysiologic mechanisms of DGBI, the concept of neuromodulation, and the rationale for treatment.

An approach that includes the evaluation of anxiety specifically related to each DGBI, effect on quality of life, and behavior toward the disease is recommended. Examples of specific anxiety include fear of having a cardiac comorbidity in FCP, fear of food triggers in FD, fear of bowel movements in IBS, or fear of accidental stool leakage when outside of the home in fecal incontinence (FI). This requires communication skills, as well as a good doctor-patient relationship that enables validating, empathizing, providing trust, conceptualizing behavior, educating, and discussing management options.218 In Germany, a cross-sectional study examined the doctor-patient relationship through conversations and validated questionnaires on difficult doctor-patient relationships. A total of 520 physicians and 5,354 patients participated, and among the hypotheses on the development of DGBI, the physicians mainly suspected burdens related to stress as the cause in the majority of cases (65.4%), whereas patients more often felt that the main reasons for their symptoms were food (55.4%) or other somatic causes (43.6%). Functional and/or somatoform symptoms led to difficult interactions more often than “somatic” symptoms, and to the perception of patients as time-consuming. Even though the physicians reported taking enough time to speak to their patients with DGBI, only one-third completely agreed they had enough time, and only 5% felt sufficiently compensated by those conversations with patients.219 Good communication in medical care correlates with better adherence by the patient (OR 1.62), compared with poor communication.220 Interpersonal interventions improve communication in the doctor-patient relationship. This was demonstrated by a systematic review of RCTs and controlled observational studies that evaluated interpersonal doctor-patient interventions in 73 studies, reporting that up to 67% of interventions were directed toward the physician. The impact on patient experience was measured and there were improvements in patient satisfaction, a patient-centered experience, and a decrease in unmet needs, which often corresponded to a positive impact on other patient health outcomes, such as quality of life, depression, and adherence. Improved interpersonal interactions positively impacted physician wellbeing, burnout, stress, and confidence in communicating with difficult patients.221

In their analysis on communication skills, the Rome group concluded that evidence supports the fact that interventions targeting patient-physician interaction improve population health and the patient-physician experience, and training in communication skills was the most common intervention, leading to better communication, satisfaction, and perception of physician approachability. They recommend a series of 5 practical points: 1) preparation with intent before seeing the patient, 2) listening intently and entirely, 3) formulating an agreed agenda with the patient as to what matters most, 4) connecting with the patient’s story, and 5) exploring emotional cues by naming and validating the patient’s feelings.13 Taking the time to explain the pathophysiologic mechanisms behind DGBI, the concept of neuromodulation, the mechanisms of action of the medication, the rationale for its use, and the expected response is recommended. This will improve the understanding of its pharmacologic value, reducing the stigma attached to neuromodulator use, and most likely increase treatment adherence.2

• •

  Screening for depression and anxiety in all patients with DGBI, using self-rated scales (HADS, PHQ-9, or GAD-7), is recommended.

An important association between DGBI and primary affective disorders has been described.218 Given that symptoms may overlap between entities, cognitive and affective symptoms are key in the differential diagnosis. Our group of experts found no validation studies using the hospital anxiety and depression scale (HADS) in IBS or other DGBI populations. However, it has been validated in Mexico in other GI entities with a high prevalence of depression and anxiety, such as inflammatory bowel disease (IBD).222 On the HADS, 20 to 23 points represents moderate symptoms and a score above 24 points signifies severe symptoms. The PHQ-9 patient health questionnaire has been validated in a Mexican population for major depressive disorder screening, and a score of 10 or more indicates a moderate-to-severe depressive episode that requires starting treatment with an antidepressant.223 The GAD-7, developed by the World Health Organization (WHO), established a cutoff point above 10 for moderate-to-severe anxiety that requires anxiolytic neuromodulators. These same cutoff points have been validated in international populations with IBS.224

• •

  Consultation with mental health professionals (psychiatry/psychology) is recommended for patients with DGBI and moderate-to-severe depression or anxiety, patients using central acting agents at the neuromodulation dose, and patients with eating disorders.

• •

  When there is a moderate-to-severe depressive episode, without treatment for DGBI, gradual titration of the neuromodulator is recommended until reaching the minimum effective dose. If atypical antipsychotics, delta-ligands, or azapirones are used, or there is intolerance to TCAs or mirtazapine, combination with a SSRI at an antidepressive dose is suggested.

Depressive symptoms, as well as major depressive disorder and anxiety disorders are frequent comorbidities in DGBI. The average overall prevalence of major depressive disorder and anxiety disorder as comorbidities associated with IBS is 15.2% and 20.7% respectively, but up to one-third of the patients with DGBI may develop symptoms of anxiety and/or depression. Evidence supports a higher risk of presenting with anxiety and depression before and after the diagnosis of a DGBI, particularly within the first year of diagnosis, as well as greater GI symptom severity associated with the comorbidity. The relationship between DGBI with depression and anxiety appears to be bidirectional. The mechanisms behind that relationship include low-grade inflammation, altered vagal signaling, and alterations in central and peripheral neural signaling.225,226 It is important to know the minimum effective dose of central neuromodulators for treating depression in gastroenterology.227

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  We recommend a multidisciplinary approach to and management of DGBI associated with affective and somatic disorders. Training physicians to have knowledge of these associations, with the support of mental health professionals, is suggested.

• •

  Health professionals should adopt a more comprehensive and patient-centered approach, considering both physical symptoms and psychologic and behavioral aspects, and severity predictors, such as alexithymia, persistent somatization, and demoralization, should be detected.

• •

  The use of validated and accessible evaluation instruments (PHQ-15 and SCL-90) is recommended.

Somatization is the tendency to experience and communicate somatic discomfort in response to psychosocial stress and consequently seek medical help.228 In the diagnostic and statistical manual of mental disorders (DSM-5), the category of somatoform disorders of the DSM-4-TR was replaced by somatic symptom disorders and related disorders.229 The change is the identification of a physical symptom associated with significant discomfort and decline. Somatic symptom disorder underlines the importance of basing the diagnosis on the presence of positive signs and symptoms, such as the response to distressing somatic symptoms with abnormal thoughts, feelings, and behaviors, eliminating the criterion of absence of a medical explanation for the somatic symptoms.230 There are studies that identify mental health as a strong predictor of perceived difficulty in the doctor-patient relationship, particularly in patients with multi-somatoform disorders, with an OR of 12.3 of being perceived as difficult.219 The application of a structured interview with revised diagnostic criteria for psychosomatic research (DCPR-R) showed that IBS symptoms were more intense when associated with psychologic comorbidities, such as alexithymia (46.8%), persistent somatization (34%), and demoralization (19.7%), with a 3-times higher prevalence of somatic symptom disorder (PHQ-12) and hypochondriasis (Whiteley index). In addition, both alexithymia and persistent somatization were predictors of severe somatic symptoms.231 A systematic review identified 40 scales for evaluating somatic symptoms, concluding that the PHQ-15 and the symptom checklist (SCL-90) were the best options for use in large-scale population studies because of their psychometric characteristics and low burden to participants.232 Diagnostic evaluation in patients with DGBI and those comorbidities are suggested, along with professional conduct recommendations.233

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  We recommend nonpharmacologic interventions as part of the comprehensive care for DGBI.

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  We recommend the promotion of self-management programs to identify specific triggers, as well as the implementation of self-control strategies for managing stress.

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  We recommend different forms of psychotherapy (cognitive behavioral therapy, gut-directed hypnotherapy, mindfulness, and psychodynamic interpersonal therapy), according to patient characteristics and goals.

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  We recommend working on effective physician communication skills, essential for a solid and trusting relationship, to aid the patient in accepting recommendations and feeling comfortable with the referral to a mental health specialist.

Behavior-based therapies are short, personalized, nonpharmacologic interventions focused on GI symptoms and based on skills that improve said symptoms and the psychologic comorbidity.2,234 They may be combined with other neuromodulation and behavioral therapies, offering comprehensive and targeted therapy for DGBI.18,235

The Rome Foundation recommends different nonpharmacologic interventions for the treatment of DGBI:236

• 1

  Self-management programs. They promote self-care and trust in the ability to control health and may lead to GI and psychologic symptom improvement, as well as better quality of life. They emphasize the identification of triggering factors, such as diet, exercise, and stress, as well as stress management through self-management training, available in pamphlets or manuals.

• 2

  Cognitive behavioral therapy (CBT). A technique that focuses on modifying behaviors and dysfunctional thought patterns, CBT helps patients unlearn maladaptive coping skills developed in response to GI symptoms or stress. Several RCTs have described the efficacy of CBT in DGBI, and even though an inclusion criterion in most of them was at least 4 sessions, a program of a minimum of 10 sessions (range 12-16) is recommended. Traditionally, sessions are taken in a setting of person-to-person direct contact, but currently they can be group-based, with minimal contact, or internet-delivered via an online application (app).234,237–239 In a meta-analysis of psychologic therapies for IBS, CBT proved to be effective, whether self-administered, with minimal contact, or face-to-face, carried out by telephone, or through an online app (RR 0.61, 95% CI 0.45-0.83).240

• 3

  Gut-directed hypnotherapy. A technique developed by Whorwell et al.241 in 1984, it is a form of medical hypnosis where the patient is placed into a heightened state of openness to specific suggestions, usually during a series of 7-12 weekly sessions for at least 3 months, with frequency depending on the severity of each case. It can be delivered on an individual basis or via groups or video calls, at the office, or at home. Most of the evidence on its usefulness in DGBI comes from a number of studies on IBS.242,243 The current protocol for at-home hypnosis was developed by Palsson and Whitehead in 1994.244 During each session, a trained physician induces a heightened state of focus and awareness to increase openness to personalized post-hypnotic suggestions, focused on gut-brain dysregulation, directed at reducing the attention to and perception of abdominal pain and the impact of stress on symptoms, and increasing the sensation of control over symptoms. There is solid evidence of its efficacy in IBS, with more than 15 RCTs and a meta-analysis reporting it to be superior to education and routine therapy (symptom persistence RR 0.67, 95% CI 0.49-0.91),234,240 and evidence on other DGBI has recently started to emerge.245

• 4

  Mindfulness. This practice can be described as the desire to be grounded in the moment, accepting pain or painful sensations or emotions as inevitable,234 which can help to reduce suffering and stress and improve the regulation of emotions. Patients are instructed to observe and identify details of their symptoms, without passing judgement or reacting to triggers, and the primary aim is not symptom reduction, but rather their identification and acceptance. Due to their stress-sensitive nature, symptoms can be lessened when learning to remain steady and calm in the face of stressful situations. Mindfulness therapy has been shown to be effective in a wide range of conditions by reducing stress, improving the regulation of emotions, and reducing visceral hypersensitivity. Clinical studies have reported that mindfulness may improve specific GI symptoms, such as constipation, diarrhea, bloating, and anxiety. A meta-analysis described the usefulness of mindfulness therapies in different DGBI.246 For examples of mindfulness therapy exercises, see the Appendix B link, to access the audio supplementary material.

• 5

  Psychodynamic-interpersonal therapy. Offered by a trained psychotherapist, this therapy is based on a solid and trusting relationship for repairing negative emotions associated with DBGI. There is evidence of its benefits in functional somatic syndromes, IBS, and dyspepsia.247

Several meta-analyses have evaluated the benefit of the different psychotherapy or psychologic therapy options, including psychoeducation, self-help, cognitive therapy, psychodynamic psychotherapy, hypnotherapy, mindfulness therapy, and relaxation therapy in IBS, reporting NNTs of 2248 and 4.185 In the two most recent studies that included 41 RCTs and more than 4,072 patients, the most effective psychologic interventions that also had the largest number of trials and patients were self-administered or minimal contact CBT, in-person CBT, and gut-directed hypnotherapy. However, none of them showed superiority over the other. The most effective long-term interventions were those based on CBT and gut-directed hynotherapy.240,249

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  The use of nonpharmacologic neuromodulation devices, such as transcutaneous auricular vagus nerve stimulation (taVNS) may be considered in FD, GP, and IBS.

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  Continuous sacral nerve stimulation (CSNS), percutaneous/transcutaneous tibial nerve stimulation (PTNS/TTNS), and translumbar and transsacral magnetic neurostimulation (TLTSMNS) may be considered in FI.

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  CBT administered via digital apps or virtual reality (VR)/extended medical reality (EMR) may be considered in FD and IBS.

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  Music therapy (MT) may be considered for associated anxiety disorders.

Various external devices have recently been developed that function as nonpharmacologic neuromodulators. Transcranial alternating current stimulation (tACS) is a form of non-invasive brain stimulation capable of modulating phasic neural activity and central descending pathway transmission, which can induce neuromodulation and neuroplasticity, restoring neuro-intestinal signaling homeostasis.250–252 Several external tACS devices have been evaluated for different DGBI, including transcranial vagus nerve stimulation (tVNS), transcranial cervical vagus nerve stimulation (tcVNS), transcranial auricular vagus nerve stimulation (taVNS), transcutaneous electrical acustimulation (TEA), transabdominal electrical stimulation (TES), sacral nerve stimulation (SNS), percutaneous tibial nerve stimulation (PTNS), translumbar and transsacral magnetic neurostimulation (TLSMNS). In recent years there has been evidence of preliminary improvement with taVNS in FD, CVS, and FCP.253–255 Most of the evidence of benefits of taVNS in DGBI comes from two studies on FD. The first showed that two taVNS sessions were superior to sham therapy at 2 weeks, for reducing symptom scores and anxiety and depression scales, improving gastric accommodation, and increasing efferent vagus nerve activity and the percentage of gastric slow waves.256 A more recent study included 300 patients with FD (Rome IV) assigned to two different taVNS groups (10 Hertz, 25 Hertz, or placebo) for 4 weeks. Response rates, defined as a decrease of more than 5 points in the daily symptom score (81.2% vs 75.9% vs 47%, respectively, p < 0.001), and adequate improvement (85.1% vs 80.8% vs 67%, p < 0.05) were significantly superior in the two treatment groups, compared with placebo.257 TEA reduced symptom intensity in FD in 55% of patients at 2 weeks,258 whereas in another study, it improved quality of life scores, gastric accommodation, and gastric emptying.259 Both taVNS and tVNS have been evaluated in GP, and decreased nausea severity and improved symptoms of nausea and vomiting, satiety, fullness, bloating, and abdominal pain were reported with taVNS.259,260 TEA has also been evaluated in IBS-C, and showed an increase in the number of complete spontaneous bowel movements, being the first study to report that finding. It also showed an improvement in abdominal pain scores.261 Another study reported similar findings with taVNS, which improved quality of life scores and had a beneficial effect on bowel movements and pain.262 At least three forms of neurostimulation have recently been evaluated, showing success in FI: SNS, PTNS, and TLSMNS. In general, they reduced the weekly number of FI episodes, episodes of fecal leakage, and improved quality of life.263–268

Digital technology has transformed the way in which we communicate and access information on any topic. Therapeutic interventions based on technology have evolved in recent years, helping in the prevention, management, and treatment of different medical problems. Symptom questionnaires and self-applicable scales, as well as recreational and relaxation programs that include varied forms of psychotherapy, are now accessible through different digital apps.269 CBT and hypnotherapy administered online or via digital apps, with visual aids, videos, and at-home exercises, have been shown to have similar results to in-person CBT, with a reduction in symptom severity, as well as nausea, abdominal pain, and bloating scores in subjects with FD or IBS, albeit with no control groups or blinding.269,270 The development of those apps, with the support of artificial intelligence, appears to optimize response time and reduce the number of sessions.271

A technology called virtual reality (VR) has recently emerged. VR is a computer-generated depiction of a three-dimensional (3D) environment that makes the users feel as if they are part of a virtual environment, with motion sensors integrated into the device that adjust the image when the person moves and limit the capacity to process and be aware of the harmful stimuli and sensations outside of the virtual world. In medicine, VR has been evaluated, showing success for the treatment of experimentally induced pain and somatic pain. In the United States, the Food and Drug Administration has renamed it “extended medical reality” (EMR). VR/EMR has recently been incorporated into relaxation techniques and psychotherapy modalities, such as CBT, for the treatment of DGBI, particularly FD and IBS.272–274 In the first study evaluating VR in FD (Rome IV), patients were assigned to VR and a control group with videos of nature in 2D, every day for 2 weeks. In addition to being safe, VR was associated with improved symptom and quality of life scores.273 In IBS, an initial validation study reported that a standardized 8-week CBT program administered through VR might help patients manage their symptoms.274 This emerging technology is growing, and most certainly in the coming years there will be more evidence on the use of VR in other DGBI.

Musical therapy, or music therapy (MT), is reported to be associated with pleasure, which can alter brain biochemistry, inducing the release of different neurotransmitters and hormones, such as dopamine, serotonin, and oxytocin,275 with a beneficial effect on motivation, stress reduction, and social affiliation, in addition to effects of reduced anxiety and improved quality of sleep.276,277 Functional neuroimaging studies have shown that music induces analgesia through several mechanisms, such as the modulation of descending pathways, and has effects on the circuits associated with emotion, such as the amygdala and the cingulate cortex.278 A recent study reported that two MT strategies, an active improvised one, and a receptive one, for 50 minutes twice a week for 3 months, was associated with reduced depression scores.279 Another study compared the effect of MT versus no therapy on the use of sedatives during endoscopic examinations, and the authors found that the group in MT had lower anxiety scores, greater tolerance, and less propofol use during their procedures.280 Lastly, a meta-analysis of 14 controlled studies published in 2017 reported that MT was associated with reduced pain in conditions associated with chronic pain, with no fixed exposure or duration strategy in the majority of the studies.281